The number of patients with diabetes mellitus has been increasing steadily owing to the recent change in the lifestyle. According to the research done in 1997 in Japan, it has been speculated that the number of people diagnosed as possibly having diabetic mellitus is 6.9 million, and the number of people who cannot be ruled out the possibility of diabetes mellitus is 6.8 million. Most of the patients with diabetes mellitus in Japan are classified into type 2 diabetes mellitus, wherein the basal pathological conditions thereof are the reduced output of insulin and the insulin resistance, and medicaments against to each condition have been developed.
Sulfonylurea (SU) agents, which have long been known, and widely used for improving the reduced output of insulin, however, have been known to have a risk of hypoglycemia as a serious side effect, and further to maybe cause obesity to patients.
On the other hand, thiazolidinedione agents have been known as an insulin resistance improving agent.
Troglitazone was put on market first as a thiazolidinedione agent, but it induced a serious hepatic damage, by which the selling thereof was discontinued. In Japan, pioglitazone has been used clinically at the present, but the heart failure due to the increase in circulating plasma volume was reported as a serious side effect thereof, and hence, Urgent Safety Information on pioglitazone was issued on October, 2000, which announced that pioglitazone needs careful attention to heart failure and edema. As to rosiglitazone, which has been widely used in the western countries, there are reported side effects such as infection of upper respiratory tract, anemia, edema, weight gain, etc., and a thiazolidinedione agent having no concern regarding hepatitis damage or side effects on the cardiovascular system has not been put on the market yet.
Thiazolidinedione agents have been thought to exhibit anti-diabetic activity by activating PPARγ. It is known that PPAR has subtypes such as α, γ, δ (β), etc., and fibrate agents (e.g., clofibrate, fenofibrate, etc.), which have been used as antidyslipidemic agent, have been considered to exhibit their pharmacological activities by activating PPARα. It has recently been reported that the insulin resistance is improved by administering a PPARα activator to animal models (cf., Journal of Biological Chemistry, vol. 275, p 16638, 2000), and there is a growing possibility where PPARα activators may show an effectiveness against not only hyperlipidemia but also diabetes mellitus.
Many of compounds activating PPARγ or both PPARα and PPARγ such as isoxazolidediones are reported other than thiazolidinedione agents (cf., Journal of Medicinal Chemistry, 43, p. 527, 2000), but the efficacy and safety thereof in the clinical field are not confirmed yet. At the present, PPARα agonists, PPARγ agonists, PPARα/γ agonists or PPARα/γ activation regulators having a good antidiabetic activity and high safety have been desired.
In addition, diabetic medicines having a pyrrole group have been known (cf., JP-A-2002-121186, WO 02/085851, WO 2004/048341), but the efficacy and safety thereof in the clinical field are not reported yet.